| Project/Area Number |
23K11841
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 90110:Biomedical engineering-related
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| Research Institution | Kawasaki Institute of Industrial Promotion Innovation Center of NanoMedicine |
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Principal Investigator |
ディリサラ アンジャネユル 公益財団法人川崎市産業振興財団(ナノ医療イノベーションセンター), ナノ医療イノベーションセンター, 主任研究員 (70794353)
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| Project Period (FY) |
2023-04-01 – 2026-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2025: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2024: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2023: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | Sinusoidal blockade / Cytokine therapy / Liver toxicity / Tumor immunotherapy / Interleukin-12 / Messenger RNA / Lipid nanoparticle |
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| Outline of Research at the Start |
This study aims to (i) avoid off-target liver expression and prolong intratumoral retention of IL-12, (ii) identify predominantly transfected cell fractions in the liver and tumor upon mRNA-LNP treatment before and after PEG coating, (iii) exploit tumor-selective IL-12-lumican in synergy with ICPI therapies to develop a cure for intractable superficial (e.g., melanoma) and deep (e.g., pancreatic cancer) cold solid tumors without systemic toxicity.
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| Outline of Annual Research Achievements |
To avoid severe liver toxicity of lipid nanoparticle (LNP) loaded with mRNA encoding toxic payloads, we selectively stealth-coat the liver sinusoids with PEG to suppress the LNP capture by the liver. Our strategy dramatically suppressed the hepatic expression of luminescent protein and maintained high tumor-to-liver protein expression efficiency upon direct intratumoral injection of mRNA-loaded LNP. Currently, we are heading to apply our liver stealth coating strategy to avoid the liver accumulation of LNP while predominantly expressing the same toxic protein selectively and preferentially in the tumor for effective immunotherapy.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We successfully decreased the model luminescent protein expression from messenger RNA-loaded lipid nanoparticles in the liver by in situ stealth coating to liver sinusoids. On the contrary, our technology maintained similar protein expression in the tumor with and without liver sinusoidal stealth coating. Now, we are extending this technology to stop the liver accumulation of lipid nanoparticles loaded with mRNA encoding toxic proteins to alleviate the liver damage from toxic proteins expressed from mRNA.
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| Strategy for Future Research Activity |
1.A single-chain mRNA encoding interleukin-12 (combining p35 and p40 subunits) will be designed as a model mRNA encoding toxic payload.
2. Quantification of IL12 expression in tumor and liver after and before liver sinusoidal stealth coating.
3.Blood chemistry analysis before and after intravenous administration of liver sinusoidal stealth coating agent and intratumoral injection of lipid nanoparticle encapsulated mRNA encoding IL12.
4.Antitumoral activity of IL12 mRNA-loaded lipid nanoparticle with and without liver sinusoidal coating.
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